Abstract There is strong evidence that chronic heavy alcohol use is a major risk factor for adverse cardiovascular events in middle age, but the atherosclerotic processes that underlie heart disease and stroke are often initiated much earlier in life as the result of potentially modifiable, unhealthy lifestyle behaviors. Binge drinking, or high quantity drinking episodes that spike blood alcohol concentration, is a high-risk lifestyle behavior that is prevalent in emerging adult and college populations. Decades of animal and human research have established that individual drinking episodes evoke dynamic physiological, neural, and behavioral responses, but how and when these biobehavioral adaptations to individual drinking episodes transition into chronic dysfunction and disease is not known. This R01 application seeks to understand how drinking-related cardiovascular injury is instigated and how it progresses. It derives from our recently completed NIAAA-funded R21 project that produced new methodologies for studying human, preclinical cardiovascular dysfunction, identified underlying physiological mechanisms that link behavior to cardiovascular activity, and differentiated cardiovascular functioning in college-aged binge drinkers versus moderate/non-drinkers. This application builds on our foundational work by proposing a longitudinal study of ostensibly healthy college students (n=300) with weekly tracking of drinking behaviors for two years and cardiovascular assessments prior to and following this drinking assessment period. The goal is to better capture the progression of binge drinking effects on specific cardiovascular control systems and on the coordination across these systems. This proposal innovates through its conceptual and methodological approach to quantifying drinking ?dose? and preclinical cardiovascular ?response?. Specifically, it proposes a weekly longitudinal assessment of drinking behaviors to capture details of individual drinking episodes, including the severity (estimated drinks per occasion), frequency (times per week), and pacing (intervals between binges) of these episodes. It further proposes to non-invasively measure drinking-related injury to vascular and cardiac control systems under different loading paradigms (parasympathetic, sympathetic, and cognitive challenge tasks) and utilizes more sensitive measures to improve detection of subtle cardiovascular change. Aim 1 seeks to identify early cardiovascular biomarkers of binge drinking. Aim 2 will prospectively monitor detailed alcohol use data over two years and link drinking behaviors to changes in these biomarkers. Aim 3 will explore whether binge drinking moderates the relationship of cardiovascular functioning to cognitive performance. The use of a systems biology framework to identify early cardiovascular biomarkers of high-risk drinking has far-reaching public health implications, as it may provide a new tool for identifying alcohol-related cardiovascular harm long before the emergence of clinical illness or disease state.